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Polymer-lipid delivery vehicles

a technology of polymer lipids and delivery vehicles, which is applied in the direction of drug compositions, capsule delivery, heavy metal active ingredients, etc., can solve the problems of significant solubility problems, high water insoluble, and delivery vehicle formulations of organic active agents

Inactive Publication Date: 2006-08-10
CELATOR PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017] The delivery vehicles described herein provide favorable pharmacokinetics and effective delivery of biologically active agents that are relatively insoluble in water. The delivery vehicles are emulsions of nanoparticles with a hydrophobic polymeric core which may contain the biologically active agent surrounded by a protective layer which is amphiphilic and thus prevents aggregation or precipitation of the particles and inhibits association of the particles with protein in plasma or serum. The vehicles may be prepared by a method previously not contemplated for the preparation of nanoparticles.
[0027] Generally, this method allows for an encapsulation efficiency of the active agent in the range from about 50 to about 99%.

Problems solved by technology

Highly water-insoluble organic drugs have significant solubility issues and generally require co-solubilization agents and / or premedication to ameliorate side effects encountered during administration and long infusion periods.
Delivery vehicle formulations of organic active agents often suffer the disadvantages that they exhibit “unsatisfactory entrapment efficiency”; poor stability; unacceptable delivery primarily to the liver and spleen; poor plasma pharmacokinetics; rapid dissociation of active agent; and anti-tumor activity that is modest or not improved at all (Sharma, et al., Cancer Letters, (1996) 107:265-272; Sharma, et al., Int. J. Cancer (1997) 71:103-107; Crosasso, et al., J.
A significant obstacle to the use of these injectable drug delivery materials is the rapid clearance of the materials from the bloodstream by the monophagocytic system (MPS).
Further obstacles are issues of effective size, stability and drug retention.
According to this disclosure, other phospholipids such as phosphatidyl inositol and phosphatidyl glycerol are unworkable in this system.
Despite the substantial number of preparations of nanoparticles designed for drug delivery, an ideal composition has not been achieved.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0104] The Preparation of PCL Nanoparticles Stabilized by DPPC / DSPC / DSPE-PEG Mixtures

[0105] Nanoparticle systems containing DPPC / DSPC / DSPE-PEG2000 (45:45:10 mole ratio) and incorporating Taxol® were prepared using the method of the present invention. Poly(caprolactone) (PCL) was selected as the hydrophobic polymer making up the core of the particle. The nanoparticles were coated with a stabilizing lipid / PEG-lipid mixture during particle formation. In this method, the polymer and drug are dissolved in a solvent that is partially miscible with water and then mixed with an aqueous solution containing the lipid. The mixture is then homogenized, diluted with water while vortexing and dialyzed. In order to prepare lipid-coated nanoparticles by this method, it was necessary to dissolve the stabilizing lipid (lipid and PEG-lipid solution) in an ethanol / water mixture rather than water alone. The stability of the nanoparticles was assessed by measuring the size and polydispersity of the part...

example 2

[0111] PCL Nanoparticles Cannot be Stabilized in the Absence of Stabilizing Lipid such as PEG-Lipid

[0112] In order to determine whether the presence of a stabilizing lipid such as DSPE-PEG was required for the preparation of lipid-coated PCL and PLA nanoparticles, nanoparticles were prepared in the absence of PEG-lipid, employing only DMPC or DPPC as the lipid coating.

[0113] The method was repeated in the same manner as in Example 1 to prepare PLA nanoparticles coated with DMPC and PCL particles coated with DPPC. PLA or PCL was dissolved with Taxol® at a 1:30 weight ratio in a 1 mL solution of 1:1 v / v benzyl alcohol:ethyl acetate. For the preparation of both nanoparticles, the drug and polymer precipitated out during the general procedure and therefore no size measurement could be obtained. These results thus indicate that stabilizing lipids, such as PEG-lipid conjugates are required in these systems to produce PCL or PLA nanoparticles that are stable in vitro. Examples of stabili...

example 3

[0114] The Preparation of PCL Nanoparticles Stabilized by PVA / DSPE-PEG Mixtures

[0115] The inventors next examined whether the in vitro stability of the PEG-lipid-coated nanoparticles could also be enhanced by the addition of a hydrophilic polymer surface stabilizer, poly(vinyl alcohol) (PVA). PVA contains a hydrophobic, hydrocarbon backbone that allows it to stably associate with the hydrophobic core of the particles, while the hydrophilic portion of the polymer extends into the aqueous medium. PVA of a molecular weight of 10,000 g / mole was employed in order to minimize the viscosity of the system during particle preparation, as higher molecular weight PVA may result in an increase of the solution viscosity leading to an increase in particle size.

[0116] Stock solutions of 100 mg / mL PCL in ethyl acetate, 10 mg / mL Taxol® in ethyl acetate and 5% w / w poly(vinyl alcohol) (PVA) in water were prepared. A DSPE-PEG750 stock solution at a concentration of 100 mg / mL was prepared in ethanol. ...

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Abstract

Delivery vehicles comprising nanoparticles which are composed of: (a) a biodegradable hydrophobic polymer forming a core, and; (b) an outer amphiphilic layer surrounding the polymer core containing a stabilizing lipid are suitable for delivering active agents.

Description

TECHNICAL FIELD [0001] This invention is directed towards vehicles comprising nanoparticles for delivery of drugs, especially hydrophobic drugs. BACKGROUND ART [0002] Drug delivery vehicles including lipid-based delivery vehicle systems have been extensively developed and analyzed for their ability to improve the therapeutic index of drugs by altering the pharmacokinetic and tissue distribution properties of drugs. This approach is aimed at reducing exposure of healthy tissues to therapeutic agents while increasing drug delivery to a target site. [0003] Considerable effort has been devoted to the development of novel approaches for the delivery and administration of organic active agents including hydrophobic drugs. The clinical utility and economic potential of hydrophobic drugs are well established. Highly water-insoluble organic drugs have significant solubility issues and generally require co-solubilization agents and / or premedication to ameliorate side effects encountered durin...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K9/10A61K47/34A61K31/00A61K31/337A61K31/4745A61K31/704A61K31/7048A61K31/7072A61K31/7076A61K33/24A61K47/24A61K47/32A61P35/00
CPCA61K9/0019A61K9/127A61K9/1271A61K9/1272A61K9/5138A61K9/5146A61K31/00A61K31/337A61K31/4745A61K31/704A61K31/7048A61K31/7072A61K31/7076A61K33/24A61K2300/00A61P35/00
Inventor ALLENWEBB, MURRAYTARDI, PAULYUAN, YUMIN
Owner CELATOR PHARMA INC
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